The present invention concerns polymer microcapsules and, more particularly, the preparation of gas-filled polymer microcapsules that are useful in medical applications such as diagnostic imaging.
It is well known in the medical arts that ultrasound imaging is a useful diagnostic tool for studying the cardiovascular system and internal organs of the body. Ultrasound imaging is most effective with the use of ultrasonic contrast agents that enhance signal strength. Ultrasound contrast agents should be nontoxic, injectable intravenously, sufficiently small as to be capable of passing through the pulmonary, cardiac and capillary circulatory systems, stable during recirculation, and capable of being removed from the body, e.g., biodegradable. Gas-filled microbubbles suspended in a liquid are exceptionally efficient ultrasound reflectors and have therefore been the subject of much study over the past 25 years.
Drawbacks to the use of free gas microbubbles include the difficulty of controlling their bubble size distribution, particularly when injected into the circulatory system, and their limited long-term stability in use. Gas-filled microbubble suspensions that are not free gas microbubbles may be prepared in aqueous media using one or more surfactants via sonication or similar methods such as described in Wheatley et al. U.S. Pat. No. 5,352,436 and in Hilmann et al., U.S. Pat. No. 4,466,442. Gas microcapsules or microballoons, which are air or gas bodies surrounded or encapsulated by a membrane wall, have also been developed in an effort to provide imaging contrast agents with improved properties.
Gas microcapsules made by sonication procedures and encapsulated with a water insolubilized biocompatible material such as albumin, a heat-sensitive protein, are described in Feinstein, U.S. Pat. No. 4,774,958, Widder et al., U.S. Pat. No. 4,844,882, and Cerny et al., U.S. Pat. No. 4,957,656. Albunex.RTM. contrast agent (available from Molecular Biosystems, Inc., San Diego, Calif.) is a commercially available ultrasound contrast agent that is a suspension of stabilized air microbubbles encapsulated with albumin.
Gas-filled microcapsules may also be prepared by other techniques, such as forming a dispersion of gas microbubbles in an aqueous medium containing a wall-forming material and inducing direct microencapsulation of the microbubbles, as described in PCT International Patent Publications WO 95/23615 and WO 92/18164. Gas-filled microcapsules may also be prepared by forming a membrane or shell around a volatile core material in an aqueous medium or water/oil emulsion and thereafter removing the volatile core material, such as described in European Patent Application EP-A1-0 458 745 and PCT International Patent Publication WO 91/12823. The gas-filled microcapsules described in these references are prepared in aqueous-based systems which place constraints on the nature of the wall-forming material that may be used. The volatile core utilized in these methods is typically a volatile oil (although WO 91/12823 mentions the possible use of solid cores) and is formed during the preparation of the microcapsules, so precise control of the core sizing is difficult to achieve.
A need exists for a simple manufacturing method for preparing gas-filled microcapsules within precisely controlled size specifications using a wide range of wall-forming materials.